title: 7,3',4'-Trihydroxyisoflavone, a metabolite of the soy isoflavone daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4.
abstract: Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.
authors.affiliation: World Class University, Biomodulation Major, Department of Agricultural Biotechnology, Seoul 151-921, Republic of Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Nury
authors.initials: N
authors.lastname: Song
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Lim
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: G Tim
authors.initials: GT
authors.lastname: Bowden
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007529:Isoflavones / Q000737:chemistry* / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000517:prevention & control*; D010936:Plant Extracts / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000517:prevention & control*; D013025:Glycine max / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D007529:Isoflavones; D016328:NF-kappa B; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; C004742:daidzein; D051546:Cyclooxygenase 2; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; C061213:3',4',7-trihydroxyisoflavone